Advances in Anatomic Pathology:
Recurrent Hepatitis C and Acute Allograft Rejection: Clinicopathologic Features With Emphasis on the Differential Diagnosis Between These Entities
Moreira, Roger Klein MD
Department of Pathology and Cell Biology, Columbia University Medical Center, New York Presbyterian Hospital
The author has no funding or conflicts of interest to disclose.
Reprints: Roger Klein Moreira, MD, 630W 168th Street VC14-238B, Surgical Pathology, New York, NY 10032 (e-mail:email@example.com; RamirezDC@cshs.org).
Chronic hepatitis C virus infection is the leading etiology for liver transplantation in the United States. Recurrent hepatitis C occurs nearly universally in these patients and represents a serious posttransplantation complication. Despite the detailed characterization of the histologic features of both recurrent hepatitis C and acute cellular rejection (ACR) over the last decades, the pathologic distinction between these 2 conditions remains one of the greatest diagnostic challenges in liver pathology. An accurate diagnosis, nevertheless, plays an essential role in patient management, as different therapeutic strategies are used for these conditions. In this review, the clinicopathologic features of posttransplantation recurrent hepatitis C and ACR are discussed, with emphasis on distinguishing histopathologic features, morphologic variants, ancillary techniques, and diagnostic pitfalls.
Chronic hepatitis C virus (HCV) infection is currently the leading etiology of end-stage liver disease and the most common indication for liver transplantation in the United States. Recurrent infection after liver transplantation is universal and the vast majority of patients eventually show histologically manifested hepatitis C. Acute cellular rejection (ACR), similarly, remains a common complication in this population, especially in the early posttransplantation period. An accurate diagnosis of ACR is particularly important in HCV-infected patients, as increased immunosuppression has been shown to accelerate HCV-induced liver damage and decrease graft and patient survival.1 Conversely, treatment for recurrent hepatitis C using interferon-based therapy has been associated with allograft rejection in some studies.2–4 Liver biopsy, therefore, plays a key role in patient management. Although the histopathologic features of both recurrent hepatitis C and ACR are well described, the distinction between these 2 conditions is fraught with problems and remains extremely challenging in practice. Excellent comprehensive reviews of the differential diagnosis of liver dysfunction in the posttransplantation setting have been published elsewhere.5–8 In this review, the main clinicopathologic findings of recurrent hepatitis C and ACR are discussed, with emphasis on distinguishing histologic features, morphologic variants, and potential diagnostic pitfalls.
RECURRENT HEPATITIS C
In patients with chronic hepatitis C, allograft infection by circulating virions occurs immediately after transplantation.9–11 After a transient period of decreased viremia (mainly during the “anhepatic” phase and during HCV entrance into graft hepatocytes and reticuloendothelial system), HCV ribonucleic acid (RNA) levels increase rapidly and reach pretransplantation levels in approximately 72 hours.12 At steady state, HCV viral load is typically 10 to 20 times higher than in the pretransplantation period.13–15 Acute hepatitis is frequently accompanied by mild transaminase elevation due to immune response against infected hepatocytes.9,16 Unlike native liver acute HCV infection, however, spontaneous viral clearance has not been documented in the posttransplantation setting.17
Histologic manifestations of acute allograft infection usually appear sometime between 4 and 12 weeks, although histologically apparent HCV infection has been reported to occur as early as 9 days post transplantation.12,16 In its earliest form, histologic features of recurrent hepatitis C consist of increased numbers of apoptotic hepatocytes (acidophilic bodies), sometimes associated with lymphocytic lobular inflammation, lobular disarray, and Kupffer cell hypertrophy. The lobular findings in the acute phase of recurrent hepatitis C are usually mild. Prominent lobular inflammation with confluent or bridging necrosis, or predominantly centrilobular injury are not typical of recurrent HCV infection and should raise suspicion for alternative diagnoses, including rejection, drug toxicity and, in the late posttransplantation period, alloimmune hepatitis. Portal changes during the acute phase are minimal to absent. Lymphocytic cholangitis and bile duct epithelial changes, if present, are focal and mild.
As recurrent hepatitis C becomes histologically established (usually 3 to 6 mo after transplantation or later), chronic portal inflammation and interface hepatitis develop. In addition, mild-to-moderate ductular reaction, a relatively uncommon finding in chronic HCV infection in native livers, is often present in posttransplantation biopsies (Table 1). These changes characterize the histologic transition to a “chronic hepatitis” pattern and are demonstrated in 70% to 90% of recipients within 1 year and in 90% to 95% of patients within 5 years of transplantation.17
The portal inflammation in chronic hepatitis C in native livers is composed predominantly of mature lymphocytes. When portal lymphoid aggregates are present, sometimes forming germinal centers (Fig. 1 A), CD20+ B cells represent the main population, accompanied by a small number of CD4+ T-helper cells and a network of scattered follicular dendritic cells. The remainder of the portal and interface inflammatory infiltrate is composed predominantly of CD4+ T cells, with a smaller population of CD8+ T cells.18 In liver allografts, lymphocyte aggregates and germinal centers are seen in some cases but are less common and prominent compared with native livers. Scattered plasma cells are often present but are not conspicuous. Clusters and sheets of plasma cells are not features of typical recurrent HCV infection and should raise the possibility of alloimmune/rejection phenomena (as discussed below).
The lobular inflammation is composed predominantly of CD8+ T lymphocytes that are often seen clustering around acidophilic bodies. A variable amount of Kupffer cell hyperplasia is also common. The lobular findings in chronic recurrent HCV infection are generally similar to those seen in the native liver, although more severe degrees of inflammation have been reported by some investigators (Table 1).19,20 Saxena et al21 also described a significantly higher number of acidophilic bodies in posttransplantation recurrent hepatitis C (mean of 606±101 acidophilic bodies/cm2) compared with chronic hepatitis C in native livers (mean of 194±21 acidophilic bodies/cm2). Mixed microvesicular and macrovesicular steatosis is also typically present in chronic hepatitis C, both in native livers and allografts. In most cases, fat accumulation is mild-to-moderate in severity and lack the predominantly centrilobular distribution of nonalcoholic fatty liver disease.22,23 Steatosis in the setting of HCV infection is mechanistically linked to insulin resistance, except in patients with genotype 3 infection, in whom a direct viral effect on hepatocyte lipid metabolism is thought to play an important role. Steatosis is often prominent in the latter cases.24 In the posttransplantation period, immunosuppressive medications, including corticosteroids and calcineurin inhibitors, may also contribute in the pathogenesis of steatosis.25
Rejection-Like Features in Hepatitis C
The recognition of rejection-like features of chronic hepatitis C in native livers is important for interpretation of posttransplantation biopsies. There are, however, obvious inherent difficulties in studying “rejection-like” features due to recurrent hepatitis C in the posttransplantation setting, as a minor component of rejection can never be excluded with certainty. Consequently, the best available evidence comes from the study of hepatitis C in native livers.
The presence of bile duct damage in the setting of viral hepatitis—or Poulsen-Christoffersen lesion23—was reported in “non-A, non-B” chronic hepatitis by Lefkowitch and Apfelbaum26 and, later, in chronic hepatitis C by several investigators,27–29 with prevalence ranging from 28% to 91% of cases. More recently, Souza et al30 reported bile duct damage in 30% of liver biopsies from native livers of patients with chronic hepatitis C. Therefore, bile duct injury seems to be a relatively common finding in otherwise typical chronic HCV infection, albeit usually mild and involving only a minority of portal tracts (Fig. 1B). Endotheliitis, previously thought to represent a rejection-specific phenomenon, is now known to occur in HCV infection (Fig. 1C). Souza et al30 identified portal and central vein endotheliitis in 20% and 0% of cases, respectively. In another study by Yeh et al,31 the prevalence and severity (score 0 to 4) of endotheliitis was assessed in native livers with various chronic liver diseases. The investigators reported portal endotheliitis score >1 in 60% and score 3 in 20% of chronic hepatitis C patients, whereas severe (score 4) endotheliitis was not seen in this group. Interestingly, both bile duct damage and endotheliitis were more common in patients with more severe degrees of portal inflammation or hepatitis activity index scores in the latter studies.30,31 The presence of portal eosinophils, similarly, may be difficult to interpret in the setting of recurrent hepatitis C after liver transplantation. In the nontransplant literature, Tarantino et al32 detected an eosinophilic portal/periportal infiltrate (defined as≥3 cells per biopsy) in 31% of liver biopsies of HCV-infected patients, whereas Souza et al30 reported portal eosinophils (defined as ≥2 eosinophils in 1 portal tract or 2 portal tracts with at least 1 eosinophil) in 42% of samples (Fig. 1D). In posttransplantation biopsies, a small number of portal eosinophils is also a common finding in otherwise typical cases of recurrent hepatitis C. Therefore, most of the features commonly evaluated to diagnose ACR can also be seen, albeit to a lesser degree, in chronic hepatitis C.
Fibrosing Cholestatic Hepatitis C
Originally described in immunosuppressed patients with chronic hepatitis B, fibrosing cholestatic hepatitis (FCH) is now well described in patients with HCV infection (FCH-C). FCH-C is thought to represent an aggressive form of viral hepatitis C occurring in severely immunosuppressed patients, including liver33–35 and other solid organ transplant recipients,36,37 and individuals with human immunodeficiency virus/HCV coinfection,38 among other situations. Nowadays, FCH-C is most commonly diagnosed in liver transplantation patients—a growing population in whom viral hepatitis C and immunosuppression often coexist. Zekry et al39 have shown that the typical TH-1 immune response (mainly interleukin-2, interferon-γ, and tumor necrosis factor-α) to HCV in both native livers and allografts is replaced by a TH-2 response (mainly interleukin-4 and interleukin-10) in FCH. The lack of an HCV-specific immune response in these patients leads to uncontrolled viral proliferation and extremely high intrahepatic viral loads.39,40 Contrary to conventional HCV infection, direct viral cytopathic effect is thought to play an important role in the pathogenesis of FCH.16,39,41 Clinically, the development of posttranplantation FCH has been associated with overimmunosuppression, often after treatment of allograft rejection. Patients present with severe, progressive cholestatic liver disease and extremely high HCV viral loads (typically >30 to 50 million IU/mL ).42 In a recent study—the largest series reported to date—FCH was diagnosed in 1.7% (17 of 973) of patients transplanted for hepatitis C. This study confirmed the very poor prognosis associated with this variant of recurrent hepatitis C, with a mean of 7.8 months from FCH diagnosis to either death or retransplantation.43
Histopathologically, FCH-C is characterized by significant portal inflammation35,41,44 which is generally similar to that of typical recurrent hepatitis C (Fig. 2A). This is in contrast with FCH-B, in which portal inflammation is minimal or absent.41 Prominent bile ductular reaction causing portal tract expansion, simulating biliary obstruction, is a characteristic finding (Figs. 2A, B). Sinusoidal (or pericellular) fibrosis is an unusual pattern of fibrosis in hepatitis C that is often present in a periportal distribution in FCH (Fig. 2C). Hepatocyte ballooning (with or without significant lobular inflammation) may be prominent and is thought to reflect direct HCV viral cytopathic effect.16,39,41 Cholestatic changes, encompassing intracellular and canalicular cholestasis and also feathery degeneration of hepatocytes (cholate stasis) are also present in most cases (Fig. 2D). The latter finding has been shown to represent the earliest recognizable pathologic feature of FCH-C by Dixon and Crawford.35 Although not specific individually, none of the above features are particularly common in typical recurrent hepatitis C, and the presence of a combination of several of these findings is highly suggestive of FCH.
The International Liver Transplantation Society consensus panel45 has suggested the following criteria for the diagnosis of FCH-C: (1) longer than 1 month after transplantation (usually <6 mo); (2) serum bilirubin >6 mg/dL; (3) characteristic histologic features, including centrilobular hepatocyte ballooning, paucity of inflammation, and variable degrees of cholangiolar proliferation; (4) “very high” serum HCV RNA levels; and (5) absence of biliary complications (normal cholangiogram) and absence of hepatic artery thrombosis. All of the above features should be present to make the diagnosis. These criteria, however, are largely based on small case series and personal experience of the members of the panel. The pathologic criteria, in particular, which represent a key component of the diagnosis of FCH, are only broadly outlined and may reflect some features observed primarily in FCH-B. As discussed above, significant amount of portal and lobular inflammation is a relatively common feature in cases of FCH-C and should not preclude this diagnosis. In addition, in a retrospective review of 27 well-characterized cases of posttransplantation FCH-C at our institution, hepatocyte ballooning was frequently present diffusely throughout the lobule rather than showing a predominantly centrilobular distribution (unpublished data). Most importantly, the number of pathologic features necessary for a diagnosis of FCH is unclear. Precise histopathologic criteria for this entity, therefore, are yet to be defined.
Other Unusual Findings
Additional uncommon histopathologic findings in chronic hepatitis C include granulomatous inflammation and hepatocyte giant cell transformation. Giant cell transformation of hepatocytes similar to that seen in the pediatric population (neonatal hepatitis and biliary atresia) and in postinfantile giant cell hepatitis has been reported in 2.6% of native liver biopsies from HCV-infected patients in 1 study, typically showing a centrilobular distribution. The majority of the patients in this series had HCV-human immunodeficiency virus coinfection, but giant cell transformation was also documented in the setting of HCV infection alone.46 It is unclear whether giant cell transformation is also seen in post transplantation recurrent hepatitis C. Hepatic granulomas are present in a small minority of HCV-infected patients without evidence of other diseases, both in native livers47 and allografts.48
Disease Progression Post Liver Transplantation
Even in its typical form, recurrent hepatitis C is characterized by a significantly more aggressive clinical course than HCV infection of native livers, with 10% to 30% of patients progressing to cirrhosis after 5 years of transplantation and over 40% after 10 years.17,19,49–51 Studies evaluating serial biopsies report fibrosis progression of 0.3 to 0.6 stages/year (using a 4-tiered system) in the posttransplantation setting compared with 0.1 to 0.2 stages/year in nontransplant patients.52–57 This translates into an average time from transplantation to cirrhosis of approximately 9.5 years compared with an average of 30 years from infection to cirrhosis in native livers (Table 1).17
The more aggressive natural history of chronic hepatitis C in allografts compared with native livers is due to a combination of numerous factors, including immunosuppression and major histocompatibility complex mismatching (leading to impaired control of viral replication and potential alloimmune injury to the graft, respectively),9,10,16,17 and the frequent coexistence of various profibrogenic insults such as preservation/reperfusion injury, biliary complications, rejection, and other viral infections. As a result, early and rubust stimulus for activation and perpetuation of the fibrogenesis cascade is seen in HCV-infected grafts, which in turn leads to a more aggressive disease. The role of early hepatic stellate cell activation in recurrent hepatitis C was demonstrated by Russo et al58 and Gawrieh et al.59 In both these studies, increased stellate cell activation at 4-month post transplantation, as assessed by α-smooth muscle actin immunohistochemistry of biopsy samples, was predicted of fibrosis progression at 1 and 2 years post transplantation.
Two models of HCV-induced fibrogenesis progression are described.60 According to the traditional model, HCV infection and associated inflammatory response generate various inflammatory mediators, including transforming growth factor β and platelet-derived growth factor, which induce hepatic stellate cell activation, proliferation, and extracellular matrix deposition.61 A second model of fibrogenesis in HCV infection involves hepatocyte replicative arrest (characterized by an increased ratio of p21 to Ki67 expression), occurring as a consequence of chronic hepatocyte injury, as a putative trigger of ductular reaction and progenitor cell activation (an alternative pathway of hepatocyte regeneration), which in turn are associated with fibrogenesis.62,63 Telomere shortening has also been described in this setting by many investigators60,64,65 and, similarly, is thought to indicate chronic injury, increased cell-cycle turnover, and hepatocyte senescence. Although fundamentally different, these 2 models of fibrosis progression are not mutually exclusive and may, in fact, operate simultaneously in most cases.
Although the overall incidence of rejection is declining,6 20% to 40% of liver transplantation patients still have at least 1 episode of clinically significant ACR (defined as presence of histologic findings of rejection accompanied by liver enzyme abnormalities) and up to 80% of patients may show histologic abnormalities of ACR on protocol biopsies taken 1-week post transplantation.11,66,67 Several factors have consistently been associated with increased risk for ACR, including older allograft donor age (>30 y), prolonged cold ischemic time (>15 h), “healthy” recipients (young age, low Child-Pugh score, normal creatinine, etc.), human leucocyte antigen-DR mismatch, and underlying immune dysregulation (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, etc.).68–71 Whether HCV infection represents a risk for development of ACR, however, is still controversial,72,73 as some studies have shown higher risk of rejection in HCV-infected patients,71,74–76 whereas others have not.77 Diagnostic ambiguity and need for more frequent biopsies for evaluation of liver enzyme abnormalities have been pointed by some investigators as possible biases in studies in which HCV was found to represent a risk factor for ACR,75 particularly after the initial several weeks post transplantation. Clinically, patients with mild ACR are often asymptomatic. With moderate-to-severe disease, fever, enlargement and tenderness of allograft, and decreased output of pale-appearing bile may be present. Leukocytosis and eosinophilia can also be seen. Serum levels of transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin are the main tests used clinically to monitor for liver dysfunction in the posttransplantation setting. Although allograft rejection characteristically presents with a predominantly “cholestatic” pattern of liver enzyme abnormality, nonselective enzyme elevation is common. Clinical and laboratory findings lack both sensitivity and specificity for diagnosis of ACR.78
The histologic diagnosis of ACR is based on the triad of features comprising: (1) portal inflammation, (2) bile duct inflammation/injury, and (3) endotheliitis (Fig. 3). According to the Banff classification of liver allograft rejection, at least 2 of the 3 findings above must be present for diagnosis of ACR.78 The composition and intensity of portal inflammation seen in ACR is variable, but typical “rejection-type” infiltrates consist of a mixture of lymphocytes, which often show an “activated” or “blastic” appearance, accompanied by increased eosinophils (which are more conspicuous in patients treated with steroid-sparing and/or lymphocyte-depleting immunosuppressive regimens)79 and also occasional neutrophils, macrophages, and plasma cells.6 Immunohistochemical studies have shown that the lymphocyte population of portal infiltrate and foci of endotheliitis are composed mainly of T lymphocytes, with similar numbers of CD4+ and CD8+ cells. In the population of lymphocytes within the bile duct epithelium, on the other hand, CD8+ cells outnumber CD4+ cells in a ratio of approximately 5:1. A minority of the inflammatory infiltrate in ACR is composed of B lymphocytes.80
Interlobular bile ducts are one of the main targets of the immune attack against allografts. Initially, lymphocytes penetrate through the epithelial basement membrane and can be recognized among bile duct epithelial cells. Epithelial abnormalities subsequently develop as a result of inflammation and consist of nuclear enlargement and overlapping, occasional mitotic figures, and cytoplasmic vacuolization. With more severe bile duct damage, luminal obliteration occurs and small bile ducts may be difficult to recognize within the inflammatory infiltrate. More pronounced epithelial changes such as marked nuclear pleomorphism, hyperchromasia, dyspolarity, cytoplasmic eosinophilia, and atrophic appearance of ducts (collectively referred to as bile duct “senescence”) are generally indicative of early chronic rejection.78,81 The final component of the triad, endotheliitis, is characterized by lymphocytic inflammation directed to the vascular endothelium of portal veins, central veins or, less commonly, hepatic arteries. Endotheliitis may be manifested by attachment of intravascular lymphocytes to endothelial cells or by the presence of subendothelial lymphocytes (subendotheliitis) causing detachment, or “lifting,” of endothelial cells from the vascular basement membrane. In both situations, endothelial cells usually show signs of injury and partial denudation of the vascular lumen may be seen. Portal vein branches are most commonly affected, followed by central vein endotheliitis in moderate-to-severe rejection. Inflammatory or necrotizing arteritis is an uncommon finding that typically affects larger arteries near the hepatic hilum (not usually present in biopsy samples) and occurs only in the most severe cases of rejection.8,78,82,83
In the most common form of ACR, occurring early in the posttransplantation period (initial 3 mo), the portal findings described above are typically present, with centrilobular injury and central vein endotheliitis developing only as rejection progresses towards the severe end of the spectrum. The diagnosis of ACR during this period is usually straightforward. In the late posttransplantation period (beyond 3 mo of transplantation), however, variant histologic patterns of rejection become more frequent and may pose significant diagnostic difficulties (Table 2).
Demetris et al83 studied the reproducibility of individual histologic features and overall diagnosis of ACR. In this study, moderate-to-excellent interobserver agreement was reported for histologic features typically used for diagnosis of ACR (evaluated in 2 separate occasions by each of the 5 participating pathologist) [portal inflammation (κ=0.86 to 0.88), subendothelial inflammation (κ=0.39 to 0.63) and bile duct damage (κ=0.42 to 0.49)]. Intraobserver reproducibility, similarly, ranged from moderate to excellent for individual rejection features. Arteritis was seen in only 0.02% of cases and is a poorly reproducible finding. The interobserver reproducibility for overall diagnosis of ACR was good (κ=0.50 to 0.62 in 2 separate interpretations), whereas the intraobserver reproducibility was good to excellent among 5 participating pathologists (κ=0.53 to 0.89).
Central Perivenulitis and Isolated Central Perivenulitis
Central perivenulitis (CP) is a term suggested by the Banff Working Party to describe a spectrum of inflammatory changes and injury involving the centrilobular region (often without identifiable central vein endotheliitis), thought to represent a manifestation of allograft rejection in the majority of cases (Fig. 4).5 In the early posttranplantation period, CP is usually associated with typical portal findings of ACR, usually in moderate-to-severe disease (using the Banff grading system). CP, however, may also be seen in isolation or in associated with portal features that are not typical or diagnostic of ACR [referred to as isolated central perivenulitis (ICP )], especially in the late posttransplantation period, hence representing more of a diagnostic challenge. ICP is one of the most common histologic variants of ACR, detected in 28% of adult patients (10% of biopsies) and 16% of pediatric patients (9% of biopsies) in 1 study by Krasinskas et al. 84,85 ICP is seen almost exclusively in the late posttransplantation period and seems to represent the most common pattern of ACR in this time period when routine protocol biopsies are obtained. As reported for CP occurring in association with portal-based ACR, ICP is thought to be associated with adverse outcomes, including resistance to immunosuppressive therapy and subsequent development of chronic ductopenic rejection and centrilobular fibrosis.84
Although rejection is the most commonly recognized etiology of ICP, alternative causes of centrilobular injury must always be considered in the differential diagnosis in the posttranplantation setting. These include ischemia, drug toxicity, viral hepatitis (including hepatitis B and C), and alloimmune hepatitis.6,86 Careful clinical correlation is necessary for exclusion of the latter possibilities.
“Chronic Hepatitis” Pattern of Rejection
Alternatively, late-onset ACR can present as a predominantly lymphocytic portal infiltrate with paucity of eosinophils and “blast-like” mononuclear cells. In addition, bile duct injury, endotheliitis, and CP are often minimal or absent, whereas interface activity might be conspicuous (Fig. 4).6,87 This “chronic hepatitis” pattern is a well-described late-onset ACR morphologic variant that is particularly problematic to recognize in the setting of chronic viral hepatitis. This pattern likely overlaps with the so-called idiopathic posttransplantation hepatitis, believed to represent a form of rejection.
Plasma Cell-Rich Hepatitis
Chronic hepatitides resembling de novo autoimmune hepatitis (or alloimmune hepatitis), characterized by prominent interface and lobular activity with increased numbers of plasma cells are also seen, albeit infrequently, in posttransplantation patients. This entity has been recently reviewed by Guido et al.88 In particular, a plasma cell-rich, alloimmune hepatitis-like disease affecting HCV-positive patients has been described by Khettry et al89 and postulated to reflect an abnormal immune response to HCV infection. Fiel et al90 have also reported a series of similar cases, referred to as “posttransplantation plasma cell hepatitis (PTPCH)”. In the latter study, the investigators concluded that this pattern likely represents a rejection phenomenon rather than a histologic variant of recurrent hepatitis C based on several observations, including an increased frequency of antinuclear antibodies and other autoantibodies, a tendency of PTPCH to occur in patients with subtherapeutic levels of immunosuppressive medications, and a trend towards a more favorable prognosis response to increased immunosuppression (although the overall prognosis was still poor). In HCV-negative patients, de novo autoimmune/alloimmune hepatitis has been associated with production of donor-specific antibodies against Glutathione S-transferase T1 enzyme due to genetic mismatch (wild vs. null genotype) between donor and recipient. C4d staining by immunohistochemistry has been detected in the majority of these patients.91 Further investigation is needed to established whether similar findings are seen in plasma cell-rich hepatitides in the setting of posttransplantation HCV infection. Therefore, although traditionally considered a histologic variant of recurrent hepatitis C, there is evidence to suggest that immune-mediated damage (overlapping with rejection-related phenomena) represents the primary insult in plasma cell-rich hepatitis occurring in the setting of posttransplantation HCV infection.
Histologically, PTPCH shows similar features to autoimmune hepatitis in native livers. Portal tracts typically show marked chronic inflammatory infiltrate with abundant plasma cells. Interface hepatitis is a hallmark of this disease and is usually prominent. Lobular inflammation, similarly, can be pronounced, with extensive hepatocyte injury and hepatocellular resetting (Fig. 4), sometimes associated with CP and centrilobular injury.
This form of hepatitis has been reported to occur during or after interferon-based HCV treatment in several studies92–94 and is generally treated with increased immunosuppression. The prognosis of this form of hepatitis is variable but generally poor, as reported in most series.
DIFFERENTIAL DIAGNOSIS BETWEEN RECURRENT HEPATITIS C AND ACR
The distinction between recurrent HCV infection and ACR represents one of the main challenges in liver pathology. In spite of its limitations, histologic assessment of liver biopsies remains the gold standard for diagnosis of these conditions and treatment decisions are made largely based on pathology results. Moreover, the treatment for clinically significant ACR and recurrent hepatitis C are distinct and, in many regards, opposite from one another. Recurrent HCV often requires decrease in levels of immunosuppression, sometimes coupled with antiviral treatment. ACR, on the other hand, is generally managed with increased immunosuppression, either in the form of corticosteroid boluses, adjustment of doses of the current regimen, or addition of a different immunosuppressive agent. There is now compelling evidence that the use of either corticosteroids or T-cell depletion for the treatment of ACR results in significantly worse outcomes in HCV-infected patients, independently of the adverse effects of rejection itself.72 Pulse therapy with intravenous methylprednisolone, for instance, causes transient increase in HCV RNA levels (4 to 100x pretreatment levels),95 whereas OKT3 therapy has consistently been associated with earlier and histologically more severe HCV recurrence.96,97 Both forms of therapy have been shown to increase graft loss and overall mortality.1,96,97 Treatment of clinically significant ACR is nevertheless justified, given the modest but well-recognized risk of rejection-related severe graft dysfunction and progression to graft failure. Because of the deleterious effects of high levels of immunosuppression and the opposing treatment strategies utilized for ACR and recurrent hepatitis C, diagnostic errors in this situation may result in serious adverse consequences.
Despite the frequency in which the differential diagnosis between ACR and recurrent hepatitis C arises in liver transplant centers, the number of pathology-based studies addressing this issue is surprisingly limited. In 1997, Petrovic et al98 studied the histopathologic features of recurrent hepatitis C compared with those of ACR occurring in HCV-negative patients. A total of 10 features were statistically associated with ACR; these mostly included findings related to mixed portal inflammation, bile duct damage, and endotheliitis—the 3 cardinal features of acute rejection. Canalicular and zone 3 cholestasis were also significantly associated with ACR. In the latter study, portal tract inflammation with eosinophils, bile duct damage, including lymphocytic infiltration and bile duct necrosis, were reported as the most discriminatory features of ARC. The recurrent hepatitis C group, however, only included patients biopsied between 30 and 180 days posttransplantation, therefore excluding most patients with established disease. As “rejection-like” features seem to become more conspicuous with increasing portal inflammation in native livers with chronic hepatitis C according to the study by Souza et al,30 cases showing more pronounced HCV-related portal inflammation in the posttransplantation setting (ie, established chronic recurrent hepatitis) may pose even greater diagnostic difficulties.
With regard to lobular features, centrilobular inflammation and hepatocyte damage/necrosis, especially if prominent and involving most central zones in a given sample, should strongly suggest the diagnosis of ACR over recurrent hepatitis C.99 Acidophilic bodies, typically regarded as a feature indicative of recurrent hepatitis C in this context, can also represent a manifestation of ACR, particularly if present in relatively low numbers. In 1 study,21 the mean number of acidophilic bodies in recurrent hepatitis C was 606/cm2 compared with 231/cm2 in cases of ACR occurring in transplant patients without viral hepatitis. Markedly increased acidophilic bodies with associated lobular inflammation, Kupffer cell hyperplasia, lobular disarray, and diffuse hepatocyte swelling are generally indicative of hepatitis C-related injury rather than ACR.
Demetris et al99 prospectively analyzed 179 biopsies from 48 HCV-infected posttransplantation patients enrolled in an immunosuppression minimization protocol diagnosed as either ACR or recurrent hepatitis C. The “gold standard” for assessing the original biopsy diagnosis was clinocopathologic correlation, including response to therapy and also retrospective review of initial and subsequent biopsies. Even in this population at increased risk for rejection, diagnostic errors invariably involved overdiagnosis of ACR, either as a primary or secondary diagnosis. One patient in this study developed classic clinical and pathologic findings of FCH after treatment of an erroneously diagnosed episode of ACR. In an attempt to avoid misdiagnoses of ACR in cases in which recurrent HCV represents the primary insult to the allograft, the investigators recommended the use of the following criteria for the diagnosis of ACR in this setting: (1) presence of inflammatory bile duct injury in ≥50% of portal tracts; and/or (2) mononuclear perivenular inflammation with associated hepatocyte necrosis and/or dropout involving ≥50% of terminal hepatic venules (Fig. 5). Using these strict criteria, diagnosis of ACR would largely be restricted to unequivocal, usually clinically significant cases of rejection (ie, moderate-to-severe grade by the Banff classification) that are more likely to (a) represent true rejection rather than merely HCV-related rejection-like features and (b) benefit from increased immunosuppression.
Regev et al100 studied the reproducibility of the diagnosis of ACR and recurrent hepatitis C. Five liver pathologist from 3 institutions classified individual cases as (1) predominantly recurrent hepatitis C, (2) predominantly ACR, (3) mixed recurrent hepatitis C and ACR, (4) normal histology, or (5) other diagnoses. There was only slight agreement on histopathologic diagnosis among all 5 pathologists (k=0.12), whereas agreement among any 4 pathologists was fair (k=0.20). The reported intraobserver agreement ranged from slight to moderate (k=0.19 to 0.42). Analysis of individual histopathologic features, similarly, showed relatively low reproducibility for several key features in this differential diagnosis, including fair interobserver agreement for both bile duct damage and endotheliitis (k=0.36 and 0.21, respectively), moderate agreement for presence of eosinophils (k=0.47), slight agreement for acidophilic bodies (k=0.13), and moderate for interface hepatitis (k=0.43). Therefore, both intraobserver and interobserver agreement seem to be suboptimal for both overall diagnosis and evaluation of individual histopathologic features in this context, even among liver transplant pathologists.
It must be emphasized that the interpretation of a biopsy sample in this scenario must ultimately be made in light of a complete clinical history. Time post transplantatation, in particular, is an essential piece of information. The majority of rejection episodes occur during the first month post transplantation, usually showing “typical” morphology, including significant portal inflammation in most cases. Histologically apparent recurrent hepatitis C during this period, however, is uncommon, particularly if significant portal infiltrate is present, as the latter is not a pronounced feature of the acute phase of recurrent HCV infection. In fact, significant hepatitis C-associated portal inflammation, indicative of transition to chronic hepatitis, is not common before 3 to 6 months post transplantation. Conversely, rejection episodes become relatively uncommon after several months of liver transplantation—a time period when at least some changes of recurrent hepatitis C are almost invariably present. Rejection episodes during this period are often central zone-based [ie, (isolated) CP] and most commonly occur in the setting of medication noncompliance and low immunosuppression levels. Therefore, unless the appropriate clinical scenario is present, a diagnosis of ACR in the late posttranplantation period should be made with caution in the setting of chronic hepatitis C. Additional potentially useful clinical data, as previously discussed, include HCV viral load, use of HCV antiviral therapy, immunosuppression regimen and levels, and history of recent infectious complications (cytomegalovirus, epstein-barr virus, ascending cholangitis etc.) leading to therapeutic decrease in immunosuppression.
Finally, after recurrent chronic hepatitis C has been documented histologically in an individual patient, subsequent biopsies will almost invariably continue to show changes of chronic hepatitis C. The question then becomes whether sufficient rejection changes are also present to warrant treatment with increased immunosuppression. In this situation, careful quantitative evaluation of hepatitis C and acute rejection features should be undertaken (Table 3) to determine the process that is primarily responsible for the patient's liver dysfunction. In general, if significant hepatitis C-related changes are present, a diagnosis of superimposed mild rejection is difficult to establish with confidence, as these features are virtually indistinguishable from rejection-like changes caused by hepatitis C infection itself. If bile duct injury or CP with hepatocyte dropout are present in the majority of portal tracts or central zones, respectively, a diagnosis of rejection (usually moderate to severe) can safely be made (Table 3).
Immunohistochemistry and Molecular Markers
In view of the obvious difficulties in distinguishing ACR from recurrent hepatitis C on routine histopathologic examination, the utility of ancillary techniques has been investigated. Immunopathologic detection of C4d, an end-product of the activated classical complement cascade, has been shown to be a useful tool in the diagnosis of humoral rejection in various solid organ allografts, including kidney, heart, lung, and pancreas.101,102 Although pure humoral rejection in liver allografts is exceedingly uncommon, C4d has been detected immunohistochemically in at least half of ACR cases of liver allografts in most series, mostly involving portal vessels and capillaries,80,103,104 but also hepatic sinusoids.105 Musat et al106 have recently documented a higher frequency of histologically-proven ACR in a group of patients with positive donor-specific human leucocyte antigen alloantibodies and liver tissue C4d expression by immunohistochemistry. In 1 study,103 C4d was detected in liver biopsy samples of 67% of patients with ACR compared with 11.8% of patients with recurrent hepatitis C. In this study, however, the groups were largely composed of unequivocal examples of each condition, with most cases of ACR occurring in HCV-negative patients. Similarly, Lorho et al107 reported a prevalence of 33% of sinusoidal C4d staining by immunohistochemistry among patients diagnosed with ACR (in the setting of various underlying liver diseases, including hepatitis C), whereas cases diagnosed as recurrent HCV and “undetermined” (ie, features of both recurrent HCV and ACR) showed no C4d expression. However, only a very small number of patients (5 and 2, respectively) were included in the latter 2 groups. Therefore, there is strong evidence that antibody-mediated/humoral alloreactivity is commonly present in liver allograft and is frequently seen in association with typical features of ACR. Humoral alloreactivity, as assessed by C4d staining, seems to be less commonly present in cases diagnosed as recurrent hepatitis C compared with cases diagnosed as ACR in the setting of posttransplantation HCV infection. However, the usefulness of C4d staining in histologically dubious cases (ie, showing features of both ACR and recurrent HCV) and the specific C4d staining pattern (portal vs. sinusoidal) remain to be elucidated.
Semiquantitative evaluation of HCV envelope-2 (E2) protein expression by immunohistochemistry was also studied in the differential diagnosis between ACR and recurrent hepatitis C. Sadamori et al108 reported higher HCV E2 expression in cases of definite and probable recurrent HCV compared with cases of definite ACR. Detection and quantitation of HCV RNA in liver tissue samples has also been studied in this context. Gottschlich et al109 compared liver biopsy tissue HCV RNA levels in 36 liver transplant biopsies performed for evaluation of elevated liver enzymes. The investigators reported a median HCV RNA level of 10,695 copies/mg in the group classified as “definite recurrent hepatitis C” compared with 1,024 copies/mg in the “definite ACR” group (P=0.03). Similarly, biopsies classified as “probable recurrent hepatitis C” showed higher tissue levels of HCV RNA compared with those classified as “probable ACR.” Although considerable overlap existed among these groups, the investigators concluded that patients with low levels of tissue HCV RNA are unlikely to have a primary diagnosis of recurrent hepatitis C. Demetris et al99 have also investigated serum levels of HCV RNA in this scenario. As with tissue levels, marked variation in serum HCV RNA was observed among different patients and in individual patients over time. However, in patients diagnosed with moderate-to-severe ACR, serum HCV RNA were almost invariably <10 million UI/mL, whereas higher levels tended to be associated with recurrent hepatitis C, particularly in patients with the fibrosing cholestatic variant.
Although histopathologic features of ACR and posttransplantation recurrent hepatitis C are well described, the differential diagnosis between these 2 conditions remains extremely challenging in practice due to multiple factors, including the presence of HCV-induced “rejection-like” features and existence of morphologic variants of ACR that may mimic chronic viral hepatitis, especially in the late posttransplantation period. This problem is further compounded by low reproducibility of both individual histopathologic features and overall diagnosis. The available evidence strongly indicates that stringent criteria should be used to diagnose ACR in the setting of HCV infection, as the vast majority of diagnostic errors involve overdiagnosis of ACR and only moderate-to-severe ACR episodes are likely to benefit from increased immunosuppression. Immunohistochemical and molecular techniques have been evaluated as adjunct tools in this setting but are of limited utility. Finally, despite its significant drawbacks, routine histopathologic examination remains the gold standard for the distinction between ACR and recurrent hepatitis C. Further studies are needed to improve diagnostic accuracy in this scenario.
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